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SGLT-2 Inhibitor Use and Cause-Specific Hospitalization Rates: An Outcome-Wide Study to Identify Novel Associations of SGLT-2 Inhibitors
This study aimed to identify novel associations between SGLT2i use and health outcomes using real-world data. Using linked data from a nationwide diabetes registry in Australia, we compared hospitalization rates in people living with type 2 diabetes commencing treatment with SGLT2i and dipeptidyl peptidase-4 inhibitor (DPP4i) between December 1, 2013, and June 30, 2019. Cause-specific hospitalizations were categorized across three hierarchies of diagnoses (first, first three, and first four digits of International Classification of Diseases, Tenth Version, Australian Modification codes). Incidence rate ratio (IRR) and 95% ...
Source: Clinical Pharmacology and Therapeutics - February 9, 2024 Category: Drugs & Pharmacology Authors: George S Q Tan Jedidiah I Morton Stephen Wood Jonathan E Shaw Dianna J Magliano Jenni Ilom äki Source Type: research

Beyond Population-Level Targets for Drug Concentrations: Precision Dosing Needs Individual-Level Targets that Include Superior Biomarkers of Drug Responses
Clin Pharmacol Ther. 2024 Feb 8. doi: 10.1002/cpt.3197. Online ahead of print.ABSTRACTThe purpose of precision dosing is to increase the chances of therapeutic success in individual patients. This is achieved in practice by adjusting doses to reach precision dosing targets determined previously in relevant populations, ideally with robust supportive evidence showing improved clinical outcomes compared with standard dosing. But is this implicit assumption of translatable population-level precision dosing targets correct and the best for all patients? In this review, the types of precision dosing targets and how they are det...
Source: Clinical Pharmacology and Therapeutics - February 8, 2024 Category: Drugs & Pharmacology Authors: Thomas M Polasek Richard W Peck Source Type: research

Clinical implications and future prospects of levonorgestrel and piroxicam as a combined emergency contraceptive regimen
Int J Clin Pharmacol Ther. 2024 Feb 8. doi: 10.5414/CP204537. Online ahead of print.NO ABSTRACTPMID:38329915 | DOI:10.5414/CP204537 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - February 8, 2024 Category: Drugs & Pharmacology Authors: Jiawei Ke Jingrui Cai Xiaolin Liu Liwen Chen Tianhui Liu Zhipeng Ruan Chengfei Zhao Source Type: research

Comparison of vancomycin area under the curve calculated based on Bayesian approach versus equation-based approach
CONCLUSION: AUC calculated using the Bayesian software allows for calculation with samples at a non-steady state, can integrate covariates, and is interconvertible with that estimated using an equation-based calculator, which is simpler and relies on fewer assumptions. Therefore, either method can be used, considering each method's strengths and limitations.PMID:38329916 | DOI:10.5414/CP204508 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - February 8, 2024 Category: Drugs & Pharmacology Authors: Eojin Lee Uijeong Yu Ji In Park Sang-In Park Source Type: research

Phenotypic Models of Drug-Drug-Gene Interactions Mediated by Cytochrome Drug-Metabolizing Enzymes
Clin Pharmacol Ther. 2024 Feb 6. doi: 10.1002/cpt.3188. Online ahead of print.ABSTRACTGenetic polymorphisms in drug metabolizing enzymes and drug-drug interactions are major sources of inadequate drug exposure and ensuing adverse effects or insufficient responses. The current challenge in assessing drug-drug gene interactions (DDGIs) for the development of precise dose adjustment recommendation systems is to take into account both simultaneously. Here, we analyze the static models of DDGI from in vivo data and focus on the concept of phenoconversion to model inhibition and genetic polymorphisms jointly. These models are ap...
Source: Clinical Pharmacology and Therapeutics - February 6, 2024 Category: Drugs & Pharmacology Authors: Roberto Viviani Judith Berres Julia C Stingl Source Type: research

Corrections to "Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions"
Clin Pharmacol Ther. 2024 Feb 6. doi: 10.1002/cpt.3187. Online ahead of print.NO ABSTRACTPMID:38319048 | DOI:10.1002/cpt.3187 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - February 6, 2024 Category: Drugs & Pharmacology Source Type: research

Tepid Uptake of Digital Health Technologies in Clinical Trials by Pharmaceutical and Medical Device Firms
Clin Pharmacol Ther. 2024 Feb 2. doi: 10.1002/cpt.3192. Online ahead of print.ABSTRACTDigital health technologies (DHTs) can enable more patient-centric therapeutic development by generating evidence that captures how patients feel and function, enabling decentralized trial designs that increase participant inclusivity and convenience, and collecting and structuring patient-generated data for regulators to use in approval decisions alongside traditional clinical outcomes. Although a growing body of evidence has documented increasing use of DHTs in clinical trials overall, the use of DHTs in clinical trials supporting medic...
Source: Clinical Pharmacology and Therapeutics - February 3, 2024 Category: Drugs & Pharmacology Authors: Caroline Marra Ariel D Stern Source Type: research

Machine Learning-Based Prediction of Escitalopram and Sertraline Side Effects with Pharmacokinetic Data in Children and Adolescents
This study evaluated data from 288 escitalopram-treated and 255 sertraline-treated patients ≤ 18 years old to develop machine learning models to predict side effects using electronic health record data and Bayesian estimated pharmacokinetic parameters. Trained on a combined cohort of escitalopram- and sertraline-treated patients, a penalized logistic regression model achieved an area under the receiver operating characteristic curve (AUROC) of 0.77 (95% confidence interval (CI): 0.66-0.88), with 0.69 sensitivity (95% CI: 0.54-0.86), and 0.82 specificity (95% CI: 0.72-0.87). Medication exposure, clearance, and time since ...
Source: Clinical Pharmacology and Therapeutics - February 1, 2024 Category: Drugs & Pharmacology Authors: Ethan A Poweleit Samuel E Vaughn Zeruesenay Desta Judith W Dexheimer Jeffrey R Strawn Laura B Ramsey Source Type: research

Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL-17A (LY3509754): A Phase I Randomized Placebo-Controlled Study
In conclusion, despite strong target engagement and a PK profile that supported once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated.PMID:38294091 | DOI:10.1002/cpt.3185 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - January 31, 2024 Category: Drugs & Pharmacology Authors: Amita Datta-Mannan Arie Regev David E Coutant Andrew J Dropsey Joanne Foster Spencer Jones Josh Poorbaugh Carsten Schmitz Evan Wang Michael E Woodman Source Type: research

Pharmacotherapy to Improve Cognitive Functioning After Acquired Brain Injury: A  Meta-Analysis and Meta-Regression
Clin Pharmacol Ther. 2024 Jan 31. doi: 10.1002/cpt.3186. Online ahead of print.ABSTRACTCognitive impairments, common sequelae of acquired brain injury (ABI), significantly affect rehabilitation and quality of life. Currently, there is no solid evidence-base for pharmacotherapy to improve cognitive functioning after ABI, nevertheless off-label use is widely applied in clinical practice. This meta-analysis and meta-regression aims to quantitatively aggregate the available evidence for the effects of pharmacological agents used in the treatment of cognitive impairments following ABI. We conducted a comprehensive search of Emb...
Source: Clinical Pharmacology and Therapeutics - January 31, 2024 Category: Drugs & Pharmacology Authors: Ruud van der Veen Marsh K önigs Simon Bakker Andries van Iperen Saskia Peerdeman Pierre M Bet Jaap Oosterlaan Source Type: research

Network pharmacology analysis of the renal protective effects of the bracken (Pteridium aquilinum) using experimental data obtained in an avian (quail) hyperuricemia model
CONCLUSION: The steam-exploded bracken Pteridium aquilinum may provide nephroprotective benefits against hyperuricemia-induced renal damage in quails through comprehensive regulatory processes. This highlights the Pteridium aquilinum's potential as an innovative nephroprotective therapeutic and dietary solution, presenting a promising avenue for hyperuricemia and renal damage treatment and prevention.PMID:38294244 | DOI:10.5414/CP204515 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - January 31, 2024 Category: Drugs & Pharmacology Authors: Sheng Li NaiDong Chen YaQin Bu JingWen Hao HePing Huang ShaoJun Zheng Source Type: research

Predicting Clinical Pharmacokinetics/Pharmacodynamics and Impact of Organ Impairment on siRNA-Based Therapeutics Using a Mechanistic Physiologically-Based Pharmacokinetic-Pharmacodynamic Model
Clin Pharmacol Ther. 2024 Jan 28. doi: 10.1002/cpt.3160. Online ahead of print.ABSTRACTApproved and emerging siRNA therapeutics are primarily designed for targeted delivery to liver where the therapeutic gene silencing effects occurs. Impairment of hepatic/renal function and its impact on siRNA pharmacokinetics/pharmacodynamics (PKs/PDs) are yet to be mechanistically evaluated to describe the unanticipated clinical observations for this novel modality. We developed pathophysiologically relevant models for organ impairment within a physiologically-based PK-PD (PBPK-PD) modeling framework focusing on modality-specific mechan...
Source: Clinical Pharmacology and Therapeutics - January 29, 2024 Category: Drugs & Pharmacology Authors: Annie Lumen Xinwen Zhang Sandeep Dutta Vijay V Upreti Source Type: research

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression
In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK par...
Source: Clinical Pharmacology and Therapeutics - January 29, 2024 Category: Drugs & Pharmacology Authors: Xiaoyu Men Zachary L Taylor Victoria S Marshe Daniel M Blumberger Jordan F Karp James L Kennedy Eric J Lenze Charles F Reynolds Cristiana Stefan Benoit H Mulsant Laura B Ramsey Daniel J M üller Source Type: research

Concomitant Use of Sodium-Glucose Cotransporter 2 Inhibitors and Overactive Bladder Drugs and the Risk of Urinary Tract Infection
This study found a similar risk of UTIs in concomitant users of SGLT-2i and DPP-4i (weighted HR 1.08, 95% confidence interval: 0.88-1.32) with OAB drugs. In the second cohort, 2,387 and 280 new-users of SGLT-2i and GLP-1RA with OAB drugs were identified, respectively. Initiation of SGLT-2i while on OAB treatment was not associated with increased risk of UTI (0.89, 0.50-1.60), compared with initiation of GLP-1RA. These results show that the concomitant use of SGLT-2i with OAB drugs was not associated with an increased risk of UTI compared with the concomitant use of DPP-4i or GLP-1RA with OAB drugs.PMID:38284421 | DOI:10.10...
Source: Clinical Pharmacology and Therapeutics - January 29, 2024 Category: Drugs & Pharmacology Authors: Sungho Bea Hyesung Lee Sohee Park Young Min Cho Won Suk Choi Katsiaryna Bykov Ju-Young Shin Source Type: research

A Retrospective Analysis of the Potential Impact of Differences in Aggregates on Clinical Immunogenicity of Biosimilars and their Reference Products
Clin Pharmacol Ther. 2024 Jan 29. doi: 10.1002/cpt.3180. Online ahead of print.ABSTRACTAggregates, in particular high molecular weight species (HMWs), have been linked to increased immunogenicity. The current understanding on the impact of HMWs is mainly based on in vitro and nonclinical studies and there are only limited data available associating differences in HMWs in marketed monoclonal antibodies (mAbs) to clinical outcomes. Biosimilars offer a unique opportunity to study the potential association between quality parameters and clinical outcomes. We performed a retrospective evaluation to investigate the association b...
Source: Clinical Pharmacology and Therapeutics - January 29, 2024 Category: Drugs & Pharmacology Authors: Cristina Fernandez-Mendivil Niamh M Kinsella Hans C Ebbers Source Type: research